The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Cervical cancer is the third most common cancer in women worldwide, responsible for approximately 530,000 diagnosed cases and 275,000 deaths a year as of 2008. Due to the origins of most cervical cancers, it is widely considered to be a preventable disease. In the United States alone from 2004-2008, there was an average of 11,967 cases of cervical cancer, 11,500 of which were attributable to HPV infection (Gillison M L, et al. Cancer. 2008; 113: 3036-3046). All publications identified herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply Immunizations (Gardasil and Cervarix) against the most carcinogenic strains of HPV are becoming more available, in addition to Pap smears, which provide for early diagnosis and therefore better treatment outcome.
There are more than 120 Human Papilloma Virus (HPV) subtypes known today; these subtypes are further categorized into low-risk and high risk types. There are currently 15 high-risk types of which HPV 16, 18, 45, 31, 33, 52, and 58 are most prevalent. More than 70% of high-grade intraepithelial neoplasias and invasive cervical carcinomas are either HPV 16+ or HPV 18+ (Schiller J T, et al. Gynecol Oncol. 2010 June; 118(1 Suppl): S12-17). In one study over the course of 12 months, 75% of women were able to spontaneously clear their high-risk HPV infection, and over an additional 6 months another 22% were able to clear the infection on their own (Steben, M. et al. Gynecologic Oncology 107 (2): S2-S5). However, those who fail to clear the infection on their own (e.g., due to immune compromised status or unknown cause) often develop cervical cancer. While new infections can be prevented via vaccines (e.g., Gardasil and Cervarix), they are ineffective for already infected patients. The current standard of treatment for patients that develop cervical cancer is a cisplatin-based chemoradiation, which fails to cure at least 15% to 45% of bulky stage IB to IIIB patients (Dueñas-Gonzalez A, et al. Cancer Treat Rev 2003, 29:389-399). Unfortunately, there are no new and more efficacious treatments on the market for HPV.
Notably, HPV is known to integrate its DNA into a host genome and preferential sites of HPV integration have been reported (e.g., Popescu et al. Cancer Genet Cytogenet 42: 157-171. 1989). As was reported elsewhere, HPV has been shown to integrate next to the N-Myc gene (2p24) and c-Myc gene (8q24. 1) (Couturier et al., J Virol 65: 4534-4538. 1991), which can result in deregulated expression of Myc proteins. Co-amplification of HPV and c-Myc has also been observed in a newly established cervical carcinoma line (Gotoh et al., Jpn. J. Cancer Res. 82: 1252-1257. 1991). In further studies, c-Myc protein levels in cervical biopsies were determined by quantitative fluorescent immunohistochemistry, and the data suggested that c-Myc protein levels play a role in early and late cervical lesions. Prolonged overexpression of c-Myc in early lesions is thought to allow for stable amplification of DHFR, which shows increased gene amplification over time and remains an indicator of tumor progression. In other reports, expression of oncoproteins E6 and E7 in high-risk types of HPV were thought to inactivate TP53 and RB1, respectively, and thus take control of both cell cycle and apoptosis, while MDM2 was up-regulated in squamous intraepithelial lesions (Arvanitis et al., Oncol Rep. 2008 October; 20(4):751-60).
Less prevalent in cervical cancer, yet more treatment-relevant, is the amplification or over-expression of ERBB2 (Erythroblastic Leukemia Viral Oncogene Homolog 2), known more commonly as HER2/neu. ERBB2 is a proto-oncogene located on chromosome 17q12. Over-expression of ERBB2 has most commonly been linked to aggressive breast cancer, but in recent years has begun gaining traction as a biomarker for other cancers. ERBB2 has in most cases a relatively low expression in cervical cancers, and widely varying results place the range of ERBB2 expression in cervical carcinomas from 1%-42% (Rosty C, et al. Int J Gynecol Pathol 2004; 23:13-7), depending on both the study site and severity of cancer. Regardless of pervasiveness, ERBB2 expression is associated with some of the most aggressive types of cancer often resulting in poor survival rates (Berchuck A. et al. Cancer Res. 1990 Jul. 1; 50(13):4087-91), and rarity of cervical adenocarcinomas which overexpress ERBB2 were described elsewhere (Fadare, et al. International Journal of Gynecological Pathology Volume 23, Issue 4 Oct. 2004). Treatment with cervical cancer patients with humanized monoclonal antibody trastuzumab is currently under review in ERBB2+ cervical cancer patients.
Therefore, while numerous treatment options for various cancers are available, and while molecular characterization of patients' and pathogens' genomes have become more and more routine, there is still a need for a better understanding in molecular events occurring in both, the pathogen's and the patient's genome in viral associated diseases and especially viral associated cervical cancer to help tailor therapies to an individual's disease.